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Risk Factor:
Risk Factor Type: Metabolic
Current Understanding:
The evidence from observational epidemiologic studies suggests that higher levels of plasma total homocysteine (tHcy) may be associated with an increased risk of incident Alzheimer's disease (AD). This body of findings is consistent with findings from related studies of cognitive decline, of brain imaging, and of genetic polymorphisms predisposing individuals to hyperhomocysteinemia. Recent trials of the tHcy-lowering vitamins—B6, B12, and folate, however, have had mixed, predominantly null results. Further research will be required to know whether supplementation with B vitamins starting in midlife, when it could prevent chronic elevation of homocysteine over a longer span, would provide greater benefit. For a review of the putative mechanisms by which homocysteine may influence AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
Literature Extraction: Search strategy  * New *
Last Search Completed: 15 November 2013 - Last content update released on 20 Nov 2013.


Table 1:   Homocysteine - continuous, per 1-µmol/L increment
Notes These reports examine the relationship between plasma level of homocysteine and AD risk. Effect sizes are per one-µmol/L increment in plasma homocysteine.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time
Mean (SD)
(Range)
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)		 Diagnostic Assessment Covariates & Analysis Comment Paper
Hooshmand, 2010 NKP-FINMONICA-CAIDE Cohort study reporting odds ratios (ORs) 271
(62%)		 7.4 y
(detail)
12.7 (-)
( - )
(detail)		 17 1.19 1.01-1.39 0.03
*		         Caucasian
 71 (4)
( - )		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, MMSE, BMI, DBP, SM, SH, SBP‡
(detail)		 Hooshmand, 2010
Kivipelto, 2009 Kungsholmen Project Cohort study reporting odds ratios (ORs) 228
(70%)		 6.7 y
18.6 (11)
(5 - 130)
(detail)		 61 1.06 1.02-1.10 < 0.0001
*		 83 1.04 1.01-1.07 0.01
*		 Caucasian
(detail)		 81 (5)
(75 - 93)
(detail)		 Screening: DSM IIIR - dementia

AD Diagnosis: DSM IIIR
(detail)		 A, E, G, albumin, APOE234, MMSE, BMI, HGB, CRT‡
(detail)		 Kivipelto, 2009
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "albumin" (albumin), "APOE234" (APOE e2 e3 e4 genotype), "APOE4" (APOE e4 genotype), "MMSE" (baseline MMSE), "BMI" (body mass index), "DBP" (diastolic blood pressure), "HGB" (hemoglobin), "CRT" (serum creatinine), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure)
 
Table 2:   Homocysteine - continuous, per 1-log(µmol/L) increment
Notes These reports examine plasma homocysteine, modeled as a log-transformed continuous variable, in relation to AD risk. We have converted the study results to effect size per 25% increase in plasma homocysteine, using the formula, exp[ln(reported effect estimate)*ln(1.25)].  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time
Mean (SD)
(Range)
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)		 Diagnostic Assessment Covariates & Analysis Comment Paper
Luchsinger, 2004 WHICAP Incidence study reporting hazard ratios (HRs) 679
(71%)		 4.0 y
*
15.6 (-)
( - )
(detail)		 109 1.06
*		 0.95-1.19
*		 0.34
*		         Caucasian, Hispanic, African-American (Black)
(detail)		 76 (6)
( - )
(detail)		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4‡
(detail)		 Luchsinger, 2004
Ravaglia, 2005 CSBA Incidence study reporting hazard ratios (HRs) 816
(53%)		 3.8 y
(detail)
13 (7)
( - )
(detail)		 70 1.10
*		 1.05-1.16
*		 0.001
*		 112 1.08
*		 1.04-1.12
*		 0.001
*		 Caucasian
(detail)		 74 (6)
( - )
(detail)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, BMI, CVD, DM, HTN, CRT, FOL, SM, SH, VTB‡
(detail)		 Ravaglia, 2005
Seshadri, 2002 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 1092
(61%)		 8.0 y
(detail)
13 (7)
( - )
(detail)		 44 1.14
*		 1.06-1.22
*		 0.001
*		 60 1.06
*		 1.02-1.09
*		 0.007
*		 Caucasian
 76 (6)
(68 - 97)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, ALC, APOE4, BMI, DM, SM, SH, SBP, VTB, VTB6‡
(detail)		 Seshadri, 2002
Seshadri, 2002 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 935
(61%)		 16 y
*
(detail)
13 (7)
( - )
(detail)		 56 1.11
*		 1.04-1.18
*		 0.001
*		 72 1.07
*		 1.02-1.15
*		 0.01
*		 Caucasian
 68 (6)
( - )
(detail)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, ALC, APOE4, BMI, DM, SM, SH, SBP‡
(detail)		 Seshadri, 2002
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "APOE4" (APOE e4 genotype), "BMI" (body mass index), "CVD" (cardiovascular disease), "DM" (diabetes mellitus), "HTN" (hypertension), "CRT" (serum creatinine), "FOL" (serum folate), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure), "VTB" (vitamin B12), "VTB6" (vitamin B6)
 
Table 3:   Homocysteine, continuous, ordinal categories
Notes This report examines the association between ordinal categories of baseline plasma homocysteine (Hcy) and AD risk. Effect estimates are calculated per one category increase of plasma Hcy.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time
Mean (SD)
(Range)
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)		 Diagnostic Assessment Covariates & Analysis Comment Paper
Kim, 2008 Older adults in Kwangju, South Korea Cohort study reporting odds ratios (ORs) 518
(57%)		 2.4 y
Plasma Hcy concentration (μmol/L)
12.5 (5)
(1 - 50)
(detail)
34
1.03
0.77-1.38
0.84
*
45
1.08
0.83-1.41
0.57
*		 Korean
 - (-)
(65 - )		 Screening: CDR, MMSE, Neuropsych Testing, Other

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, ALC, bsln wt, DEP, DISAB, PA, CRT, VITS, VARS‡
(detail)		 Kim, 2008
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "bsln wt" (baseline body weight), "DEP" (depression), "DISAB" (disability), "PA" (physical activity), "CRT" (serum creatinine), "VITS" (supplemental vitamin intake), "VARS" (vascular risk score)
 
Table 4:   Change in homocysteine, continuous
Notes This report examines the relationship between change in homocysteine levels, modeled as a log-transformed continuous variable, and incident AD. The log-transformed exposure variable was converted, so that the ORs represent the association per 100% increase (i.e., a doubling) in the exposure variable.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time
Mean (SD)
(Range)
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)		 Diagnostic Assessment Covariates & Analysis Comment Paper
Blasko, 2008 VITA Cumulative incidence study reporting odds ratios (ORs) 309
(-)		 2.5 y
- (-)
( - )
(detail)		 90 4.20 1.60-11.00 0.003          (detail) 75 (-)
(75 - 75)		 Screening: CERAD, Neuropsych Testing, TMT

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, CHMTA, CHAB42‡ Blasko, 2008
‡ Covariates: "A" (age), "E" (education), "G" (gender), "APOE4" (APOE e4 genotype), "CHMTA" (change in medial temporal lobe atrophy), "CHAB42" (change in plasma amyloid-beta 42)
 
Table 5:   Change in homocysteine, continuous, ordinal categories
Notes This report examines the relationship between change in plasma homocysteine (Hcy) concentration, modeled as ordinal categories, and AD risk. Effect estimates are calculated per one category increase in the change in plasma homocysteine levels.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time
Mean (SD)
(Range)
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)		 Diagnostic Assessment Covariates & Analysis Comment Paper
Kim, 2008 Older adults in Kwangju, South Korea Cohort study reporting odds ratios (ORs) 518
(57%)		 2.4 y
Change in plasma Hcy concentration (μmol/L)
1.7 (5)
(<0 - 25)
(detail)
34
1.21
0.91-1.62
0.2
*
45
1.30
0.99-1.69
0.05
*		 Korean
 - (-)
(65 - )		 Screening: CDR, MMSE, Neuropsych Testing, Other

AD Diagnosis: DSM IV, NINCDS ADRDA
(detail)		 A, E, G, ALC, DEP, DISAB, PA, CRT, VITS, VARS, WTCH‡
(detail)		 Kim, 2008
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "ALC" (alcohol intake), "DEP" (depression), "DISAB" (disability), "PA" (physical activity), "CRT" (serum creatinine), "VITS" (supplemental vitamin intake), "VARS" (vascular risk score), "WTCH" (weight change)
 
Table 6:   Homocysteine - categorical
Notes These reports examine the relationship between categories of plasma homocysteine level and AD.  
  Alzheimer Disease Total Dementia  
Paper Cohort Study Type # Subjects
(% Female)		 Average Follow-up Time Exposure Distribution
# of Cases Effect Size 95% CI P-value # of Cases Effect Size 95% CI P-value Ethnicity Age at Start of Follow-up:
Mean (SD)
(Range)		 Diagnostic Assessment Covariates & Analysis Comment Paper
Hendrie, 2013 Indianapolis-Ibadan Dementia Project - Indianapolis Cohort Cohort study reporting odds ratios (ORs) 912
(70%)		 -
(detail)
Lowest quartile:         
2nd quartile:         
3rd quartile:         
Highest quartile:         
(detail)		 -
-
-
-
Total: 83		 1.00
1.25
1.85
1.52		 Ref.
0.59-2.65
0.91-2.77
0.74-3.13		 Ref.
0.55
0.09
0.27		 -
-
-
-
Total: 101		 1.00
1.16
1.78
1.41		 Ref.
0.58-2.28
0.94-3.38
0.74-2.31		 Ref.
0.31
0.08
0.67		 African-American (Black)
 77 (-)
( - )		 Screening: CSID, CERAD, Informant interview, Neuropsych Testing, Other

AD Diagnosis: DSM IIIR, NINCDS ADRDA, Other
(detail)		 A, E, APOE4, SMHX, ORGCH‡ Hendrie, 2013
Hendrie, 2013 Indianapolis-Ibadan Dementia Project - Ibadan Cohort Cohort study reporting odds ratios (ORs) 819
(64%)		 -
(detail)
Lowest quartile:         
2nd quartile:         
3rd quartile:         
Highest quartile:         
(detail)		 -
-
-
-
Total: 49		 1.00
1.07
1.30
1.97		 Ref.
0.40-2.84
0.50-3.38
0.80-4.85		 Ref.
0.89
0.58
0.14		 -
-
-
-
Total: 59		 1.00
1.27
1.39
2.19		 Ref.
0.52-3.09
0.57-3.38
0.95-5.07		 Ref.
0.6
0.47
0.07		 African
 76 (-)
( - )		 Screening: CSID, CERAD, Informant interview, Neuropsych Testing, Other

AD Diagnosis: DSM IIIR, NINCDS ADRDA, Other
(detail)		 A, E, APOE4, SMHX, ORGCH‡ Hendrie, 2013
Kivipelto, 2009 Kungsholmen Project Cohort study reporting odds ratios (ORs) 228
(70%)		 6.7 y
Lowest quartile: 25%
2nd quartile: 25%
3rd quartile: 25%
Highest quartile: 25%
(detail)		 13
8
12
28
Total: 61		 1.00
0.71
1.45
2.57		 Ref.
0.26-1.91
0.57-3.69
1.06-6.24		 Ref.
0.5
0.42
0.04		 19
14
15
35
Total: 83		 1.00
0.83
1.12
1.79		 Ref.
0.39-1.77
0.51-2.42
0.86-3.74		 Ref.
0.64
0.77
0.12		 Caucasian
(detail)		 81 (5)
(75 - 93)
(detail)		 Screening: DSM IIIR - dementia

AD Diagnosis: DSM IIIR
(detail)		 A, E, G, albumin, APOE234, MMSE, BMI, HGB, HTC, CRT, FOL, VTB‡
(detail)		 Kivipelto, 2009
Luchsinger, 2004 WHICAP Incidence study reporting hazard ratios (HRs) 679
(71%)		 4.0 y
*
≤10.5 µmol/L (mean, 10.8): 26%
10.6-15.6 µmol/L (mean, 14.1): 27%
15.7-19.7 µmol/L (mean, 17.5): 24%
>19.75 µmol/L (mean, 27.4): 23%
(detail)		 25
27
25
32
Total: 109		 1.00
1.10
0.90
1.40		 Ref.
0.60-1.90
0.60-1.80
0.80-2.40		 Ref.
0.75
0.71
0.23
*		  
 
 
 		       Caucasian, Hispanic, African-American (Black)
(detail)		 76 (6)
( - )
(detail)		 AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4‡
(detail)		 Luchsinger, 2004
Ravaglia, 2005 CSBA Incidence study reporting hazard ratios (HRs) 816
(53%)		 3.8 y
(detail)
<10.1 µmol/L: 26%
10.1 -12.5 µmol/L: 25%
12.6 -15.0 µmol/L: 23%
>15.0 µmol/L: 27%
(detail)		 8
17
14
31
Total: 70		 1.00
2.43
2.50
4.20
*		 Ref.
0.95-6.20
0.95-5.90
1.75-11.07
*		 Ref.
0.06
0.06
0.002		 13
23
21
55
Total: 112		 1.00
1.75
2.00
3.50
*		 Ref.
0.75-3.50
0.50-4.10
1.75-7.67
*		 Ref.
0.12
0.06
0.001		 Caucasian
(detail)		 74 (6)
( - )		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE234, CRT, FOL, SH, VTB‡
(detail)		 Ravaglia, 2005
Ravaglia, 2005 CSBA Incidence study reporting hazard ratios (HRs) 816
(53%)		 3.8 y
(detail)
≤15 µmol/L: 73%
>15 µmol/L: 27%
(detail)		 39
53
Total: 92		 1.00
1.96		 Ref.
1.09-3.50		 Ref.
0.02		 57
55
Total: 112		 1.00
2.16		 Ref.
1.37-4.00		 Ref.
0.001		 Caucasian
(detail)		 74 (6)
( - )
(detail)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, E, G, APOE4, CRT, FOL, VTB‡
(detail)		 Ravaglia, 2005
Seshadri, 2002 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 1092
(61%)		 8.0 y
(detail)
Lowest three quartiles: 75%
Highest quartile: 25%
(detail)		 -
54
Total: 54		 1.00
2.80		 Ref.
1.40-5.40		 Ref.
0.003		 -
77
Total: 77		 1.00
2.50		 Ref.
1.50-4.40		 Ref.
0.001		 Caucasian
 76 (6)
(68 - 97)		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, G, APOE4, FOL, VTB, VTB6‡
(detail)		 Seshadri, 2002
Seshadri, 2002 Framingham Heart Study Incidence study reporting hazard ratios (HRs) 1092
(61%)		 16 y
*
(detail)
Lowest three quartiles: 75%
Highest quartile: 25%
(detail)		 38
63
Total: 101		 1.00
1.70		 Ref.
1.00-3.10		 Ref.
0.06		 48
82
Total: 130		 1.00
1.70		 Ref.
1.00-2.80		 Ref.
0.04		 Caucasian
 68 (6)
( - )		 Screening: MMSE

AD Diagnosis: NINCDS ADRDA
(detail)		 A, G, APOE4‡
(detail)		 Seshadri, 2002
Zylberstein, 2011 Cohort of women in Gothenburg Incidence study reporting hazard ratios (HRs) 1368
(100%)		 -
(detail)
Lowest tertile: 33%
Second Tertile: 33%
Third tertile: 33%
(detail)		 -
-
-
Total: 100		 1.00
1.59
2.13
*		 Ref.
0.91-2.79
1.22-3.73
*		 Ref.
0.11
0.008		 -
-
-
Total: 151		 1.00
1.30
1.67		 Ref.
0.84-2.00
1.10-2.57		 Ref.
0.24
0.02
*		 Swedish
(detail)		 47 (-)
(38 - 60)
(detail)		 Screening: CDR, Informant interview, IQ-CODE, MMSE, Neuropsych Testing, Other

AD Diagnosis: DSM IIIR, NINCDS ADRDA
(detail)		 A, E, BMI, DBP, CRT, SM, SBP, TC, TG, VTB‡
(detail)		 Zylberstein, 2011
* Derived value.
 ‡ Covariates: "A" (age), "E" (education), "G" (gender), "albumin" (albumin), "APOE234" (APOE e2 e3 e4 genotype), "APOE4" (APOE e4 genotype), "MMSE" (baseline MMSE), "BMI" (body mass index), "DBP" (diastolic blood pressure), "HGB" (hemoglobin), "SMHX" (history of smoking), "HTC" (holo-transcobalamin), "ORGCH" (member of the original cohort), "CRT" (serum creatinine), "FOL" (serum folate), "SM" (smoking status), "SH" (stroke history), "SBP" (systolic blood pressure), "TC" (total cholesterol), "TG" (triglycerides), "VTB" (vitamin B12), "VTB6" (vitamin B6)